title: Inhibition of colonic tumor growth by the selective SGK inhibitor EMD638683.
abstract: BACKGROUND
  The serum and glucocorticoid inducible kinase SGK1, which was originally cloned from mammary tumor cells, is highly expressed in some but not all tumors. SGK1 confers survival to several tumor cells. Along those lines, the number of colonic tumors following chemical carcinogenesis was decreased in SGK1 knockout mice. Recently, a highly selective SGK inhibitor (EMD638683) has been developed. The present study explored whether EMD638683 affects survival of colon carcinoma cells in vitro and impacts on development of colonic tumors in vivo.
  
  
  METHODS
  Colon carcinoma (Caco-2) cells were exposed to EMD638683 with or without exposure to radiation (3 Gray) and cell volume was estimated from forward scatter, phosphatidylserine exposure from annexin V binding, mitochondrial potential from JC-9 fluorescence, caspase 3 activity from CaspGlow Fluorescein staining, DNA degradation from propidium iodide staining as well as late apoptosis from annexin-V FITC and propidium iodide double staining. In vivo tumor growth was determined in wild type mice subjected to chemical carcinogenesis (intraperitoneal injection of 20 mg/kg 1,2-dimethylhydrazine followed by three cycles of 30 g/L synthetic dextran sulfate sodium in drinking water for 7 days).
  
  
  RESULTS
  EMD638683 treatment significantly augmented the radiation-induced decrease of forward scatter, increase of phosphatidylserine exposure, decrease of mitochondrial potential, increase of caspase 3 activity, increase of DNA fragmentation and increase of late apoptosis. The in vivo development of tumors following chemical carcinogenesis was significantly blunted by treatment with EMD638683.
  
  
  CONCLUSIONS
  EMD638683 promotes radiation-induced suicidal death of colon tumor cells in vitro and decreases the number of colonic tumors following chemical carcinogenesis in vivo.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Syeda T
authors.initials: ST
authors.lastname: Towhid
authors.forename: Gui-Lai
authors.initials: GL
authors.lastname: Liu
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Ackermann
authors.forename: Norbert
authors.initials: N
authors.lastname: Beier
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Scholz
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuchß
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Toulany
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Rodemann
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use*; D018938:Caco-2 Cells; D053148:Caspase 3 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005434:Flow Cytometry; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology* / Q000627:therapeutic use*; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D001549:Benzamides; D053148:Caspase 3; D006834:Hydrazines; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C569030:EMD 638683